Periostin contributes to differential sex-linked gene expression during infarct healing

Periostin (Postn) is a matricellular protein that plays a crucial role in cardiac fibrosis following myocardial infarction (MI). However, the role of Postn in infarct healing to date has been derived from experiments conducted exclusively on male animals, leaving its sex-specific functions unaddressed. Thus, we investigated the sex-specific role of Postn in acute wound healing and extracellular matrix (ECM) remodeling post-MI using a Postn knockout (KO) mouse model. Survival analysis revealed increased mortality in male Postn KO mice compared with that of females post-MI. qPCR analysis of the infarct scar showed that Postn was required for the increased expression of structural collagen (<i>Col1a1</i> and <i>Col3a1</i>), collagen fibrillogenesis (<i>Fmod</i>), collagen stabilization (<i>Lox</i>), collagen synthesis (<i>Plod2</i>), and alpha-smooth muscle actin (<i>Acta2</i>) genes in males, whereas in females, the regulation of these genes occurred independently of Postn post-MI. We note that fibromodulin protein levels were higher in female Postn KO mice than in males, suggesting a putative protective role. Transcriptomic analysis revealed distinct gene expression patterns between sexes and phenotypes, with male Postn KO infarct scars showing the greatest dysregulation of genes, characterized by increased expression of ECM-related genes and suppressed mitochondrial-related gene expression, whereas female Postn KO infarct scars exhibited increased mitochondrial-related gene expression and reduced expression of fibrosis-associated genes. These findings emphasize sex as a biological variable in Postn actions in heart and highlight distinct molecular mechanisms underlying male and female infarct healing.<b>NEW & NOTEWORTHY</b> We determined that cardiac wound healing following MI is periostin (Postn) dependent in male mice but Postn independent in female mice. To date, previous Postn knockout (KO) studies have exclusively used male animals. The current experimental design includes both sexes and reveals that the underlying mechanism of action to be sex dependent. Specifically, changes in the expression of collagen synthesis and cross-linking genes in the infarct scar are dependent on Postn expression in males only.